As the population ages, late-onset Alzheimer's disease (AD) is becoming an increasingly important public health issue. AD disproportionately affects women. Of the more than 5 million people in the United States afflicted with this disease, two-thirds are women. Women with AD have more neuropathology than men with AD, have more severe cognitive symptoms, and more severe neurodegeneration, suggesting that the disease affects male and female brains in different ways. Thus, a focus on sex differences in AD is essential to move the field towards effective interventions. The identification of sex-specific genetic drivers of AD neuropathology and cognitive decline could transform the way treatments are administered, and be a critical step towards personalized interventions for AD. Research from both our group and others has begun to uncover genetic factors that explain some of the observed discrepancies between males and females, specifically in terms of neuropathology and cognitive decline. To advance the field, additional genetic effects must be discovered and the underlying mechanisms of sex-specific pathways of injury must be examined. The objective of this project is to identify and replicate genetic effects that act in a sex-specific manner to drive the neuropathological presentation and clinical progression of AD. The present proposal will advance our understanding of sex- specific genetic contributors to AD by leveraging 8 existing in vivo biomarker cohorts (n=3,433) and 6 existing autopsy cohorts (n=4,821) to assess genetic associations with AD neuropathology and cognitive decline. The outcome of this project will highlight new candidate pathways, and begin the process of characterizing the mechanisms by which genetic variation among males and females affects the risk and clinical symptoms of AD. The sex-specific pathways identified will offer therapeutic targets and help move the field towards personalized interventions that consider an individual's sex and neuropathological presentation.